Islet transplantation offers a potential treatment for type 1 diabetes (T1D) that could normalize blood glucose levels and circumvent the development of diabetes-associated complications. Despite recent advances in islet isolation and immunosuppressive regimens, many islet recipients gradually lose islet function after transplantation. Because islets can up-regulate their production of insulin, measurements of blood glucose, insulin C-peptide production and 1st phase insulin release detect the loss of islet function only after a significant number of islets have already been lost. It has long been hoped that transplanted islets could be directly imaged, so that their survival could be longitudinally monitored in recipients, allowing clinicians to tailor therapies to more effectively support islet survival post-transplantation. The noninvasive imaging of transplanted islets in humans now appears to be feasible, and awaits translation from rodents to nonhuman primates, and then to humans. In this R21 proposal we will test the hypotheses that; 1) the viral delivery of reporter genes, followed by optical and micro-positron emission tomography (microPET) imaging, provide new modalities to noninvasively monitor islet cell mass after intraportal islet transplantation in rodents and; 2) optical and microPET imaging can detect islet rejection earlier than measurements of blood glucose and C-peptide levels. We will also evaluate whether viral infection and long-term PET reporter expression and PET imaging is deleterious to the islet graft. If this project is successful, a subsequent R33 application will attempt to extend this technology to the imaging of transplanted islets in the liver of non-human primates. Thus, the results of this proposal may provide a foundation that will lead to new tools for improving the care and treatment of those with type 1 diabetes.